Reappraisal of a Renovated Cell-free and Concentrated Ascites Reinfusion Therapy for Malignant Ascites.

BACKGROUND/AIM: Cell-free and concentrated ascites reinfusion therapy (CART) was established for refractory ascites and renovated CART (Keisuke Matsusaki (KM) -CART) has been recently developed especially for malignant ascites; however, the actual clinical efficacy of KM-CART has been rarely reported. PATIENTS AND METHODS: We performed 226 KM-CART procedures in 104 patients with malignant ascites in three hospitals from August 2013 to September 2018. Medical records were retrospectively reviewed for ascites data, related complications, symptoms before and after each CART and prognosis after the first CART. The modified Glasgow Prognostic Score (mGPS) was reviewed before every procedure, as an indicator of nutritional status. RESULTS: Pancreatic cancer was the most common indication for the KM-CART procedure, followed by gastric cancer, hepatocellular carcinoma, ovarian cancer, and cholangiocarcinoma (five major diseases). The 50% survival times of these five major diseases after the first procedure were 25, 39, 31, 49, and 33 days, respectively. The mean survival time for all patients was 73.5 days, and 75.6 days for those with the five major diseases. All patients experienced symptomatic relief, and complications were rare. Repeated KM-CART was performed in 47.1% of the patients, most often in those with ovarian cancer (66.7%). Regarding the mGPS at the first CART procedure, 89% of patients were in the group with the poorest nutritional status. Patients who underwent KM-CART three or more times had longer survival than those who were treated once or twice. CONCLUSION: Repeated KM-CART provides a survival benefit for patients with malignant ascites, even in cases of poor nutritional status.

Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.

BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.

Diagnostic Utility of 99m Tc-MDP Bone Scintigraphy for Nivolumab-Induced Inflammatory Arthritis.

ABSTRACT: Immune checkpoint inhibitors can revive exhausted helper T-cells, and inflammatory cell reactivation may cause autoimmune disease-like conditions. Drug-induced arthritis is an immune-related adverse event, but the diagnostic approach is undefined. We present the diagnostic utility of 99m Tc-MDP bone scintigraphy for nivolumab-induced inflammatory arthritis. A 67-year-old man with hypopharyngeal carcinoma presented bilateral multiple metacarpophalangeal joint pain and swelling at each nivolumab administration. Regular imaging findings were atypical for inflammatory arthritis and did not fulfill the criteria for rheumatoid arthritis. We diagnosed nivolumab-induced inflammatory arthritis based on clinical symptoms and the symmetrical moderate uptake of the affected joints on 99m Tc-MDP bone scintigraphy.

Elicitation of Inhibitory Effects for AGE-Induced Oxidative Stress in Rotator Cuff-Derived Cells by Apocynin.

Advanced glycation end-products (AGEs) play a critical supportive role during musculoskeletal disorders via glycosylation and oxidative stress. Though apocynin, identified as a potent and selective inhibitor of NADPH oxidase, has been reported to be involved in pathogen-induced reactive oxygen species (ROS), its role in age-related rotator cuff degeneration has not been well clarified. Therefore, this study aims to evaluate the in vitro effects of apocynin on human rotator cuff-derived cells. Twelve patients with rotator cuff tears (RCTs) participated in the study. Supraspinatus tendons from patients with RCTs were collected and cultured. After the preparation of RC-derived cells, they were divided into four groups (control group, control + apocynin group, AGEs group, AGEs + apocynin group), and gene marker expression, cell viability, and intracellular ROS production were evaluated. The gene expression of NOX, IL-6, and the receptor for AGEs (RAGE) was significantly decreased by apocynin. We also examined the effect of apocynin in vitro. The results showed that ROS induction and increasing apoptotic cells after treatment of AGEs were significantly decreased, and cell viability increased considerably. These results suggest that apocynin can effectively reduce AGE-induced oxidative stress by inhibiting NOX activation. Thus, apocynin is a potential prodrug in preventing degenerative changes of the rotor cuff.

Changes in bone turnover markers after discontinuing long-term glucocorticoid administration in children with idiopathic nephrotic syndrome: a multicenter retrospective observational study.

BACKGROUND: Glucocorticoids affect bone turnover. Little is known about how bone turnover changes when glucocorticoids are discontinued following long-term administration. METHODS: This retrospective observational study was conducted on the relationship between discontinuation of long-term administration of glucocorticoid and bone turnover markers (BTMs) in patients with childhood-onset idiopathic nephrotic syndrome. Serum bone alkaline phosphatase (BAP), intact procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were evaluated as BTMs. RESULTS: Thirty-eight pairs of BTMs at glucocorticoid administration and after discontinuation were analyzed in 29 patients. The median age at baseline was 12.4 (interquartile range, 9.0-14.5) years, and the median time from the onset of nephrotic syndrome was 5.9 (3.3-9.7) years. The mean period from prednisolone discontinuation to the measurement of BTMs after glucocorticoid discontinuation was 3.5 ± 1.0 months. Changes in BTMs after glucocorticoid discontinuation were modest when the daily prednisolone dose was < 0.25 mg/kg/day (ln BAP standard deviation [SD] score, p = 0.19; log intact P1NP SD score, p = 0.70; TRACP-5b, p = 0.95). When the daily prednisolone dose was ≥ 0.25 mg/kg/day, all BTMs increased significantly after glucocorticoid discontinuation (ln BAP SD score, p < 0.01; log intact P1NP SD score, p < 0.01; TRACP-5b, p < 0.01). CONCLUSIONS: Decreased BTMs can rise within a few months of discontinuing long-term glucocorticoid administration. When the administered glucocorticoid dose is low, changes in BTMs may be small. A higher resolution version of the Graphical abstract is available as Supplementary information.

Differences in cerebral blood flow measurement using arterial spin labeling MRI between patients with moyamoya disease and patients with arteriosclerotic cerebrovascular disease.

BACKGROUND: It is unclear whether the accuracy of arterial spin labeling (ASL) magnetic resonance imaging (MRI) is the same between moyamoya disease (MMD), which is known to have markedly elevated cerebral blood volume (CBV), and atherosclerotic intracranial arterial stenosis (AS), which has relatively less elevated CBV. PURPOSE: To investigate how the differences in hemodynamics affect measurement of ASL-cerebral blood flow (CBF) using ASL for patients with MMD and AS. MATERIAL AND METHODS: Fourteen MMD and ten AS patients were evaluated with ASL-MRI, magnetic resonance angiography (MRA), and 15O-gas positron emission computed tomography (PET). The regional CBF values of ASL using two post-labeling delays (PLDs; 1525 ms and 2525 ms) were compared with the PET-derived CBF, CBV, and mean transit time (MTT). Corresponding anterior circulation results were evaluated by flow territory map-based analysis. RESULTS: The correlation between the ASL-CBF values (2525 ms) and PET-CBF declined in the MMD group (r = 0.28; P < 0.01), while the AS group showed good correlation (r = 0.77; P < 0.01). In the MMD group, the ASL-CBF values (2525 ms) overestimated the PET-CBF values as the regional CBV values increased (r = 0.35; P < 0.01). When the regions of interest were divided into two subgroups according to the degree of arterial stenosis by MRA, the correlation coefficient between the ASL-CBF (2525 ms) and PET-CBF values improved (mild stenosis: r = 0.36; P = 0.06; severe stenosis: r = 0.51; P < 0.01). CONCLUSION: The accuracy of CBF measurements using ASL-MRI differed between patients with MMD and AS. The prominent increase of CBV and the degree of arterial stenosis may have affected the accuracy of ASL-CBF in patients with MMD.

Potential Role of Surgical Resection for Gallbladder Cancer in Elderly Patients.

INTRODUCTION: With the aging of the population in Japan, gallbladder cancer (GBC) in the elderly is increasing. However, the available clinical data are limited, and the optimal treatment is still controversial. The aim of this study was to evaluate the benefit of surgical resection in GBC patients ≥75 years of age. METHODS: A retrospective single center analysis of patients who had undergone surgical resection for GBC between 2000 and 2019 was carried out. Patients aged ≥75 years (elderly group, n = 24) or <75 years (younger group, n = 50) were compared. RESULTS: Both younger and elderly patients exhibited similar clinicopathological characteristics, but comorbidity in the latter was significantly greater, as was the frequency of less invasive surgery. Nonetheless, the incidence of postoperative complications was similar in elderly and younger patients. The proportion of patients receiving adjuvant chemotherapy was lower in the elderly. Overall survival of elderly and younger patients was not significantly different (65.0 vs 62.4% at 5 years, P = .600). In multivariate analysis, residual tumor status but not age was an independent prognostic factor. DISCUSSION: This study demonstrated that appropriate surgical treatment of elderly GBC patients was safe and effective, despite their having more comorbidities and lower rates of adjuvant chemotherapy than younger patients.

CD44 as a pathological marker for the early detection of calcineurin inhibitor-induced nephrotoxicity post kidney transplantation.

Long-term calcineurin inhibitor (CNI) administration causes irreversible nephrotoxicity. Therefore, early CNI-induced nephrotoxicity detection is necessary for patients who will need long-term CNI administration. There is no pathological indicator for early CNI-induced nephrotoxicity. Here, serial protocol kidney biopsy specimens from five kidney-transplant patients with severe CNI-induced nephrotoxicity were examined. We observed that the increase in CD44 expression in glomerular parietal epithelial cells (PECs) preceded the chronic pathological changes of CNI-induced nephrotoxicity such as tubular atrophy/interstitial fibrosis, arterial hyaline thickening, and focal segmental glomerulosclerosis (FSGS). This result suggests that CD44-positive PECs have pivotal roles in FSGS development in human CNI-induced nephrotoxicity as well as rodent models. CD44 could be useful as a pathological marker for early CNI-induced nephrotoxicity detection post kidney transplantation.

Cooccurrence of Alport syndrome and poststreptococcal acute glomerulonephritis with improvement after steroid administration.

It is clinically possible for patients with Alport syndrome (AS) to suffer from poststreptococcal acute glomerulonephritis (PSAGN). However, there is only one report of such a patient, and he had end-stage kidney disease. Here, we describe an 8-year-old male with X-linked AS and chronic kidney disease (CKD) stage G2. He presented with diffuse edema, gross hematuria, proteinuria, and body weight gain after streptococcal pharyngitis. Blood examination showed kidney dysfunction, hypocomplementemia, and increased anti-streptolysin-O levels. His kidney function did not improve with symptomatic treatment. Therefore, we started steroid administration on the 12th day of hospitalization. Then, his kidney function improved before he was discharged. We confirmed that his complement function had recovered at a later date. Pathological evaluation showed findings of AS and PSAGN, including cellular crescents in 3/30 glomeruli on light microscopy. In addition, electron dense deposits (EDDs) were seen in not only the visceral subepithelium but also the glomerular basement intramembrane and subendothelium, some of which were hump-like. Although AS and CKD are indicated to have a poor prognosis in PSAGN, our patient recovered after administration of steroids. Our case suggests that we can consider the administration of steroids, including pulse therapy for PSAGN, when patients have, for example, crescents on pathology, severe renal dysfunction, nephrotic proteinuria, or AS with CKD, as in our case. Kidney pathology suggested that a typical hump is not seen in patients with cooccurring AS and PSAGN. After the patient's kidney function recovered, we continued to follow him.

The effect of rituximab on the quality of life of children with refractory nephrotic syndrome.

BACKGROUND: Rituximab (RTX) is an effective treatment for maintaining remission in patients with nephrotic syndrome (NS), but there are few reports on the effect of RTX treatment on quality of life (QOL). The purpose of this study was to examine the effect of periodically repeated RTX treatment from the perspective of QOL. METHODS: We systematically assessed the QOL of pediatric patients with refractory NS and parents' perceptions of their children's QOL through a 2 year RTX treatment protocol. Pediatric patients from Hokkaido University Hospital with refractory NS who met our specific criteria were enrolled between January 2015 and December 2015. The RTX infusion was performed 4 times at 6-month intervals, followed by mizoribine administration with early discontinuation of calcineurin inhibitors. Quality of life scores were measured by the Pediatric Quality of Life Inventory version 4.0 (PedsQL) at each RTX administration and evaluated 2 years later. RESULTS: Twenty-two patients were analyzed. The patients' QOL and their parents' perceptions of their QOL improved over our 2 year treatment protocol. Nevertheless, the parents' scores were lower than the patients' scores on all scales, with slower improvement. CONCLUSIONS: Our treatment protocol showed a significant improvement of QOL in patients with refractory NS. Although the risk of the RTX treatment should be considered, the treatment is useful for patients with refractory NS.

Effect of a proton-pump inhibitor on intestinal microbiota in patients taking low-dose aspirin.

BACKGROUND AND AIM: Low-dose aspirin (LDA) administration prevents cerebral infarction and myocardial infarction, but many studies found an association with mucosal injury. Proton-pump inhibitors (PPIs) can prevent gastric and duodenal mucosal damage, but they may exacerbate small-intestinal mucosal injury by altering the microbiota. We aimed to assess the effect of PPIs on the intestinal flora of LDA users. METHODS: Thirty-two recruited patients, who received LDA (100 mg/day) but did not take PPIs, were divided into 15 patients additionally receiving esomeprazole (20 mg/day) and 17 patients additionally receiving vonoprazan (10 mg/day). On days 0, 30, 90, and 180, the microbiota of each patient was examined by terminal restriction fragment length polymorphism analysis, and the serum gastrin, hemoglobin, and hematocrit levels were measured. RESULTS: Additional PPI administration increased the proportion of Lactobacillales in the microbiota of LDA users. This trend was more prevalent in the vonoprazan group (p < 0.0001) than in the esomeprazole group (p = 0.0024). The Lactobacillales proportion was positively correlated with the gastrin level (r = 0.5354). No significant hemoglobin or hematocrit level reduction was observed in subjects receiving LDA with additional PPI. CONCLUSIONS: Additional PPI administration increased the Lactobacillales proportion in the microbiota of LDA users. The positive correlation between the gastrin level and the proportion of Lactobacillales suggested that the change in the intestinal flora was associated with the degree of suppression of gastric acid secretion. Additional oral PPI did not significantly promote anemia, but the risk of causing PPI-induced small-intestinal mucosal injury in LDA users should be considered.

Long-term clinical characteristics and renal prognosis of children with tubulointerstitial nephritis and uveitis syndrome.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare disease, especially in children. Owing to the short-term observational period and the small number of patients analyzed in previous reports, the long-term clinical and laboratory characteristics and renal prognosis of children with TINU syndrome remain unclear. METHODS: In this retrospective observational study, we enrolled 29 children with TINU syndrome from February 1990 to February 2019. RESULTS: During the median follow-up duration of 38 months, the kidney function, urinary ß2 microglobulin-creatinine ratio (U-ß2MG/Cr), and uveitis in the patients had significantly improved at 24, 6, and 36 months after diagnosis. Higher U-ß2MG/Cr was associated with longer duration of kidney function normalization. Half of the patients required uveitis treatment for 5 years after the diagnosis. CONCLUSIONS: Patients with severe low-molecular weight proteinuria at diagnosis needed a longer duration to achieve improvements in kidney function. Uveitis has a much longer treatment period than tubulointerstitial nephritis. This study demonstrates the good prognosis of children with TINU syndrome in terms of their long-term clinical and laboratory characteristics.

Distribution of Deep Gray Matter Lesions on Magnetic Resonance Imaging in Lymphomatosis Cerebri.

We herein report the distribution of gray matter lesions on magnetic resonance imaging (MRI) in two patients with lymphomatosis cerebri (LC). In our patients, the fluid-attenuated inversion recovery sequence of brain MRI demonstrated a bilateral and diffuse high signal intensity, not only in the white matter but also in the thalamus, globus pallidus, putamen, and hippocampus. Among the deep gray matter, the caudate head and putamen (striatum) were relatively spared when compared with the globus pallidus, thalamus, and hippocampus. Interestingly, we found seven previous reports of similar MRI findings, with relative sparing of the striatum, in patients with LC. This finding may be characteristic of LC and help facilitate its diagnosis. Further investigations of a larger number of LC patients are necessary to confirm these findings.

Clinical and Angiographic Features of Patients With Out-of-Hospital Cardiac Arrest and Acute Myocardial Infarction.

BACKGROUND: Sudden cardiac arrest is a serious complication of acute myocardial infarction (MI). Although in-hospital mortality from MI has decreased, the mortality of MI patients complicated with out-of-hospital cardiac arrest (OHCA) remains high. However, the features of acute MI patients with OHCA have not been well known. OBJECTIVES: We sought to characterize the clinical and angiographic features of acute MI patients with OHCA comparing with those without OHCA. METHODS: We retrospectively analyzed 480 consecutive patients with acute MI undergoing percutaneous coronary intervention. Patients complicated with OHCA were compared with patients without OHCA. RESULTS: Of the patients, 141 (29%) were complicated with OHCA. Multivariate analysis revealed that age (odds ratio [OR]: 0.8; 95% confidence interval [CI]: 0.7 to 0.9 per 5 years; p < 0.001), estimated glomerular filtration rate (OR: 0.8; 95% CI: 0.7 to 0.8 per 10 ml/min/1.73 m2; p < 0.001), peak creatine kinase-myocardial band (OR: 1.3; 95% CI: 1.2 to 1.4 per 102 U/l; p < 0.001), calcium-channel antagonists use (OR: 0.4; 95% CI: 0.2 to 0.7; p = 0.002), the culprit lesion at the left main coronary artery (OR: 5.3; 95% CI: 1.9 to 15.1; p = 0.002), and the presence of chronic total occlusion (OR: 2.9; 95% CI: 1.5 to 5.7; p = 0.001) were significantly associated with OHCA. CONCLUSIONS: Younger age, no use of calcium-channel antagonists, worse renal function, larger infarct size, culprit lesion in the left main coronary artery, and having chronic total occlusion were associated with OHCA.

Glucose metabolism disorders in children with refractory nephrotic syndrome.

BACKGROUND: Patients with refractory nephrotic syndrome (NS) are at high risk of medication-induced glucose metabolism disorders, because of their long-term use of diabetogenic medications, particularly glucocorticoids and calcineurin inhibitors (CNIs). However, there have been no comprehensive evaluations of glucose metabolism disorders in pediatric patients with refractory NS. Moreover, glucocorticoids and CNIs could not be discontinued in these patients until the effectiveness of rituximab on refractory NS was shown, and therefore, there has been limited opportunity to evaluate glucose metabolism disorders after discontinuation of these medications. METHODS: Consecutive pediatric patients who started rituximab treatment for refractory NS were enrolled. Their glucose metabolism conditions were evaluated using the oral glucose tolerance tests (OGTT) and HbA1c levels at the initiation of rituximab treatment. Patients with glucose metabolism disorders at the first evaluation were reevaluated after approximately 2 years. RESULTS: Overall, 57% (20/35) of study patients had glucose metabolism disorders, and 40% (8/20) of these patients were detected only by their 2-h OGTT blood glucose levels and not by their fasting blood glucose or HbA1c levels. Non-obese/non-overweight patients had significantly more glucose metabolism disorders than obese/overweight patients (p = 0.019). In addition, glucose metabolism disorders in 71% (10/14) of patients persisted after the discontinuation of glucocorticoids and CNIs. CONCLUSIONS: Whether the patient is obese/overweight or not, patients with refractory NS are at high risk of developing glucose metabolism disorders, even in childhood. Non-obese/non-overweight patients who are at high risk of diabetes need extra vigilance.

Association between contrast extravasation on computed tomography scans and pseudoaneurysm formation in pediatric blunt splenic and hepatic injury: A multi-institutional observational study.

PURPOSE: We aimed to examine the association between contrast extravasation (CE) on initial computed tomography (CT) scan and pseudoaneurysm (PSA) development in pediatric blunt splenic and/or liver injury. METHODS: We conducted a multi-institutional retrospective study in cases of blunt splenic and/or hepatic injury who underwent an initial attempt of nonoperative management. A logistic regression model was used to compare PSA formation and CE on initial CT scan, and the area under the receiver operating characteristic curve (AUC) with and without CE was used to assess the predictive performance of CE for PSA formation. RESULTS: Of 236 cases enrolled from 10 institutions, PSA formation was observed in 17 (7.2%). Multivariate analysis showed a significant association between CE on initial CT scan and increased incidence of PSA formation (odds ratio, 4.96; 95% confidence interval, 1.37-18.0). There was no statistically significant association between the grade of injury and PSA formation. The AUC improved from 0.75 (0.64-0.87) to 0.80 (0.70-0.91) with CE. CONCLUSION: Active CE on initial CT scan was an independent predictor of PSA formation. Selective use of follow-up CT in children who showed CE on initial CT may provide early identification of PSA formation, regardless of injury grade. LEVEL OF EVIDENCE: Prognostic and epidemiological, level III.

O-GlcNAcylation-mediated degradation of FBXL2 stabilizes FOXM1 to induce cancer progression.

O-GlcNAcylation is a dynamic and reversible post-translational modification of cytonuclear molecules that regulates cellular signaling. Elevated O-GlcNAcylation is a general property of cancer and plays a critical role in cancer progression. We previously showed that the expression of FOXM1, a critical oncogenic transcription factor widely overexpressed in solid tumors, was elevated in MKN45 cells, a human gastric cancer cell line, by the O-GlcNAcase inhibitor Thiamet G (TMG), which induces augmented O-GlcNAcylation. Here, we identified FBXL2 E3 ubiquitin ligase as a new target of O-GlcNAcylation. Consistent with the results in MKN45 cells, FOXM1 expression was increased, accompanied by its decreased ubiquitination and degradation by TMG in the other gastric cancer cell lines, including NUGC-3 cells. We found that FBXL2 ubiquitinated FOXM1, and the interaction with FBXL2 and ubiquitination of FOXM1 were reduced by TMG in NUGC-3 cells. Interestingly, FBXL2 was also ubiquitinated, which was promoted by TMG in the cells. Moreover, FOXM1 expression and cell proliferation were reduced in FBXL2-induced NUGC-3 cells, and the reductions were attenuated by TMG, indicating that FOXM1 was stabilized by O-GlcNAcylation-mediated degradation of FBXL2 to induce cancer progression. These data suggest that elevated O-GlcNAcylation contributes to cancer progression by suppressing FBXL2-mediated degradation of FOXM1.